CN101475594B - Liver targeted antivirus precursor medicament annular phosphoester and use thereof - Google Patents
Liver targeted antivirus precursor medicament annular phosphoester and use thereof Download PDFInfo
- Publication number
- CN101475594B CN101475594B CN2009100774035A CN200910077403A CN101475594B CN 101475594 B CN101475594 B CN 101475594B CN 2009100774035 A CN2009100774035 A CN 2009100774035A CN 200910077403 A CN200910077403 A CN 200910077403A CN 101475594 B CN101475594 B CN 101475594B
- Authority
- CN
- China
- Prior art keywords
- oxo
- phenyl
- chloro
- amino
- phospha cyclohexane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 C=*COC1(C[n]2c(nc(N)nc3O)c3nc2)CC1 Chemical compound C=*COC1(C[n]2c(nc(N)nc3O)c3nc2)CC1 0.000 description 1
- JXHGCUFOBQAHLQ-UHFFFAOYSA-N CC(C)COC1(C[n]2c3nc(N)ncc3nc2)CC1 Chemical compound CC(C)COC1(C[n]2c3nc(N)ncc3nc2)CC1 JXHGCUFOBQAHLQ-UHFFFAOYSA-N 0.000 description 1
- IQRYJIJAMRLIGD-UHFFFAOYSA-N CCOCC[n]1c(nc(N)nc2Sc(cc3)ccc3OC)c2nc1 Chemical compound CCOCC[n]1c(nc(N)nc2Sc(cc3)ccc3OC)c2nc1 IQRYJIJAMRLIGD-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a prodrug of an antiviral drug for use in liver of cyclic phosphate of a general formula (I) and isomers, pharmaceutical salts, hydrates, solvates and pharmaceutical compositions of the same. The invention provides uses of the compounds singly or together with other antiviral drugs in the treatment of viruses, in particular of hepatitis B viruses (HBV), hepatitis C virus (HCV), HIV viruses and/or human cytomegaloviruses (HCMV).
Description
Technical field
The present invention relates to a kind of antiviral compound, particularly relate to annular phosphate class prodrug with liver targeted antivirus effect, or its all possible isomer, hydrate, solvolyte, pharmacologically acceptable salt and pharmaceutical composition.
Background technology
Many antiviral all are known: for example emtricitabine (FTC), tynofovir (Tenofovir), LB80331, LB80317, { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid, think for (Current Drug Targets-Infectious Disorders 2005 such as card Wei, Torcitabine, NM-107, Viramidine, ribavirin, Racivir, Amdoxovir, MIV-210, PSI-6130, PSI-6206; 5,307-400; Drugs of the Future 2004,29 (2): 163-177).
Above antiviral all belongs to ucleosides; According to its chemical structure; Can simply be divided into the glycosyl end and contain two types of phosphate group and non-phosphoric acid groups, its effect base reason generally is that medicine becomes activated triphosphoric acid metabolite in the endocellular phosphorus acidifying, thereby suppresses the DNA or the rna polymerase activity of virus; Stop the synthetic of DNA or RNA, kill virus.
The glycosyl end contains the nucleotide medicine of phosphate group; Like tynofovir, LB80331 and LB80317 etc.; Be highly electronegative under physiological pH,, be difficult to arrive pharmaceutically-active target area so cell leakage is poor; It is big to be prone to be removed weak point plasma half-life, kidney and gi tract toxic side effect by kidney simultaneously, and oral administration biaavailability is poor.In order to overcome above shortcoming; The most frequently used strategy is that the phosphate group acidylate in the medicines structure is prepared into prodrug; Two (the different third oxygen acyloxy methyl) prodrug tynofovir esters of for example anti-HBV tynofovir can improve oral administration biaavailability, cell leakage and tissue distribution.But distribute in the ester hydrolase body extensively; Tynofovir ester etc. contains the ester class prodrug of phosphoric acid; Before medicine arrives liver cell; Major part has been metabolised to the parent drug that has the negative charge membrane permeability, be difficult for to arrive hepatocellular parent drug in the extracellular by the proximal tubule of active transport to kidney, and high density contains the parent drug of phosphoric acid and has certain renal toxicity.
Another kind of glycosyl end is the nucleotide medicine of phosphoric acid group not; Like emtricitabine, Entecavir etc.; Can improve cell leakage, bioavailability, toxic side effect of medicine etc.; But the glycosyl of medicine can not be metabolised to activated triphosphoric acid thing fully in cell, thereby has reduced curative effect.
The present invention is with the anti-viral nucleoside medicine: introduce 4-aryl-2-oxo-1 in the glycosyl structure of emtricitabine, tynofovir, LB80331, LB80317, { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid, Entecavir, torcitabine, NM-107, viramidine, ribavirin, Racivir, Amdoxovir, MIV-210, PSI-6130 and PSI-6206; 3; The annular phosphate structure of 2-dioxa phospha cyclohexane group is prepared into the prodrug with liver targeting.
Annular phosphate (4-aryl-2-oxo-1; 3; 2-dioxa phospha cyclohexane) 4 aryl substituents in the prodrug structure can be by CYP3A specificity catalyzed oxidation in the Cytochrome P450 isozyme family in the liver cell; The result of reaction generates a midbody that has single phosphoric acid negative charge from 4 open loops, makes it be difficult for being retained in the cell through cytolemma, again through phosphodiester enzymatic hydrolysis, β-elimination reaction; Discharge the medicine that contains aerobic phosphoric acid or carbon phosphoric acid; Continuation is changed into the ribonucleoside triphosphote medicine of biologically active by nucleoside monophosphate kinase, and another by product aryl ethylene ketone fast with liver cell in content enrich anti-oxidant and gsh radical combines to be eliminated, do not find spinoff.(J.Am.Chem.Soc.2004，126：5154-5163；J.Pharmacol.Exp.Ther.2005，312：554-560；Curr?Opin?InvestigDrugs.2006，7：109-117)。
The present invention combines to obtain one type of annular phosphate prodrug with liver targeting with above antiviral (parent drug) with small molecules carrier annular phosphate; It has high stability to gi tract, blood plasma; Be difficult for by the hydrolysis of body lactone hydrolase, after administration, arriving liver cell before can be by metabolism, and the location discharges parent drug after the entering target area is by the CYP3A metabolism in the liver cell; Make the drug level in the liver cell be higher than healthy tissues; With parent drug (like emtricitabine) or other non-liver target prodrug (like the tynofovir ester) ratio, particularly resist HBV or HCV, have curative effect height, advantage that toxic side effect is little.
Summary of the invention
The purpose of this invention is to provide the liver target prodrug that a kind of curative effect is high, toxicity is low, the antiviral location is released in the liver cell, treat and prevent the disease of various virus infectiones through small molecules carrier with liver targeting.
The inventor is through discovering; Parent drug emtricitabine, tynofovir, LB80331, LB80317, { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid, Entecavir, torcitabine, NM-107, viramidine, ribavirin, racivir, Amdoxovir, MIV-210, PSI-6130 and PSI-6206 are prepared as the annular phosphate prodrug with liver targeting; It has high stability to gi tract, blood plasma; Be difficult for by the hydrolysis of body lactone hydrolase; After administration, arriving liver cell before can be by metabolism; The location discharges parent drug after the entering target area is by the CYP3A metabolism in the liver cell, therefore can improve the drug level in the liver cell, increases curative effect and reduces toxic side effect.In addition annular phosphate compound and acid-respons are prepared salify, can increase the water-soluble of this compounds,, can improve pharmacokinetic property in its body, improve oral administration biaavailability through improving the water-soluble of compound.
The present invention provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvolyte of general formula I:
Wherein:
R
1Be selected from group with following structure:
With the corresponding ucleosides antiviral compound of above-mentioned group a-o be:
A: emtricitabine (by the exploitation of Triangle company); B: tynofovir (by the exploitation of Gilead company); C:{1-[(2-amino-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (LB80331) and d:{1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (LB80317) (by the exploitation of LG Life Sciences company); E:{2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] methane phosphonic acid (by the exploitation of Mitsubishi-Lilly company); F: Entecavir (by Bristol-Myers Squibb Co.'s exploitation); G:Torcitabine and h:NM-107 (by the exploitation of Idenix drugmaker); I:Viramidine (by the research and development of Valeant company); J: ribavirin (by the exploitation of Ribapharm company); K:Racivir (by the exploitation of Pharmasset company); L:Amdoxovir (by the exploitation of RFS Pharma company); M:MIV-210 (by the exploitation of Medivir AB company); N:PSI-6130 and o:PSI-6206 (by the exploitation of Pharmasset company).
R
2For independently being selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyanic acid, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylamino radical, C
1-C
6Haloalkyl or alkyloyl;
X for independently be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3,4;
R
1With 4 aromatic group cis or trans each other in the SULPHOSUCCINIC ACID ESTER ring structure, preferred cis-isomeride;
4 carbon atom has chirality in the SULPHOSUCCINIC ACID ESTER ring structure, and its configuration can be S or R-configuration, preferred S-configuration.
The present invention also provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvolyte of general formula I I:
Wherein:
R
3Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyanic acid, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical, C
1-6Haloalkyl or alkyloyl;
X be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
The present invention also provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvolyte of general formula III:
Wherein:
R
4Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyanic acid, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical, C
1-6Haloalkyl or alkyloyl;
X be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
Preferred compound of formula I is selected from:
(1) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(2) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(3) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(4) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(5) (2R)-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(6) (2R)-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(7) (2R)-9-{2-[4 '-(3-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(8) (2R)-9-{2-[4 '-(phenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(9) (2R)-9-{2-[4 '-(3 '-bromophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(10) (2R)-9-{2-[4 '-(3 '-fluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(11) (2R)-9-{2-[4 '-(3 ', 5 '-difluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(12) (2R)-9-{2-[4 '-(2 ', 3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(13) (2R)-9-{2-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(14) (2R)-9-{2-[4 '-(3 ', 5 '-xylyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(15) (2R)-9-{2-[4 '-(3 ', 5 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } VITAMIN B4
(16) 2-amino-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(17) 2-amino-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(18) 2-amino-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(19) 2-amino-6-hydroxyl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(20) 2-amino-6-hydroxyl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ' 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(21) 2-amino-6-hydroxyl-9-{2-[(2S ', 4R ')-4 '-(3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(22) 2-amino-6-to anisole sulfydryl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(23) 2-amino-6-to anisole sulfydryl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(24) 2-amino-6-to anisole sulfydryl-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(25) 2-amino-1,9-dihydro-9-[(1S, 3R; 4S)-4-hydroxyl-3-(2 '; 4 '-cis-(4 ' S)-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl) oxygen methyl-2-methylene radical pentamethylene]-the 6H-purine-6-one.
And all possible isomer, pharmacologically acceptable salt, hydrate or solvolyte.
The present invention also provides compound shown in the general formula I suitable pharmaceutically useful salt, hydrate or solvolyte; Wherein pharmaceutically useful salt include, but are not limited to salt that compound of Formula I become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that is become like toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, Hydrocerol A, acetate, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.The compounds of this invention can form pharmacologically acceptable salt with reactions such as alkali such as sodium, potassium, magnesium, calcium, lithiums.Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, possibly form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvolytes, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.The isomer of The compounds of this invention comprises tautomer, cis-trans-isomer, conformer, meso compound and has mapping or the optical isomer of non-enantiomorphic relationship.
Compound possibly exist with the form of cis-trans-isomer, optical isomer or tautomer among the present invention, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and compound method or three-dimensional method single-minded or asymmetric synthesis that perhaps certain isomer can various routines obtain.Since compound of Formula I is to be purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% is meant weight percent).The preparation method of pure compound not can be used to be used for the purer form of medicinal compsns.At least contain 1% in these pure inadequately products, be more suitable for 5%, better at least 10% the compound shown in general formula I or its pharmaceutically useful verivate.
The present invention also provides the preparation method of preparation compound of Formula I or its pharmaceutically useful salt, hydrate or solvolyte, describes respectively to general formula I substructure (general formula I I and general formula III) below, wherein R
1, R
2, R
3, R
4, X and n have aforesaid definition.
1. the preparation method of general formula I I compound is following:
At N, in the dinethylformamide solution, add R
3CH
2OH, 4S-phosphoramidite verivate and 5-methylthio group tetrazole are cooled to subzero 45 ℃, slowly drip tertbutanol peroxide, behind the reaction 1h, are warming up to room temperature and react 24h again, remove solvent under reduced pressure, and silica gel column chromatography obtains cis and trans general formula I I compound.
2. the preparation method of compound of formula III is following:
Method 1:
At N, in the dinethylformamide solution, add R
4OCH
2PO (OH)
2, 1, ammediol verivate, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, stirring at room 30min is warming up to about 100 ℃ and reacts 24h, reaction finishes.Reaction solution is dissolved in ETHYLE ACETATE, uses Hydrocerol A, sodium hydrogencarbonate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying removes solvent under reduced pressure, and silica gel column chromatography obtains compound of formula III.
Method 2:
With R
4OCH
2PO (OH)
2, N, the N-DEF joins in the dichloromethane solution, slowly drips oxalyl chloride, reheat is to back flow reaction 3h.Reaction solution is cooled to-78 ℃, adds triethylamine, R or S-3-aryl-1 successively, ammediol, reaction is reacted 1h after slowly being warming up to 0 ℃ behind the 1h again, drips trifluoroacetic acid, stirs 30min post-heating back flow reaction 2h, and reaction finishes.Add the neutralization of yellow soda ash frozen water solution, the organic layer washing is to neutral, and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure, and silica gel column chromatography obtains compound of formula III.
The applicant has invented preparing method's (method 2) of a kind of " cooking different foods in one pot " synthetic general formula III: with tynofovir (LB80331, LB80317 or { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid), successively with N, after N-DEF, oxalyl chloride react; Add 3-aryl-1; Ammediol prepares 4-aryl-2-oxo-1,3,2-dioxa phospha cyclohexane verivate; Use the trifluoracetic acid hydrolysis again, obtain compound of formula III.This method and the disclosed annular phosphate compound method ratio of patent CN1964967, synthesis step is few, simple to operate, yield is high, economical environment-protective, uses this novel method and has prepared one type of annular phosphate prodrug.
See embodiment about the more detailed data of preparation compound of Formula I.
The present invention also provides a kind of medicinal compsns, comprises compound of Formula I, or its isomer, pharmacologically acceptable salt, hydrate or solvolyte and pharmaceutically acceptable auxiliary, diluent or carrier.
The compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; Or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; When using with the form of pharmaceutical composition; Usually the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner are combined to process suitable administration form or dosage form, this program comprises through suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer, prodrug, pharmacologically acceptable salt, solvolyte or hydrate and at least a pharmaceutically useful carrier of general formula I.
The pharmaceutical composition of The compounds of this invention; Any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input; Or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.In addition, effectively treat central nervous system disease for the pharmaceutical composition that makes The compounds of this invention or contain it, preferably the approach medication can overcome the hemato encephalic barrier transmitance that compound maybe be low in the ventricle.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as human serum protein; Buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid, water; Salt or ionogen, like protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloided silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, like syrup, and gum arabic, sorbyl alcohol, tragacanth, or Vinylpyrrolidone polymer; Weighting agent, like lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol; Padil, lubricant, like Magnesium Stearate, talcum, polyoxyethylene glycol; Tripoli, disintegrating agent, like yam starch, or acceptable dibutyl phthalate, like bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be processed the suspension-s of water and oil, solution, and emulsion, syrup or elixir also can be processed dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, like suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup; Gel, Natvosol, CMC 99.5, aluminium stearate gel, hydrogenant food oils; Emulsifying agent, like Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (possibly comprise edible oil), like Prunus amygdalus oil, grease such as glycerine, terepthaloyl moietie, or ethanol; Sanitas is like methyl paraben or propyl ester, Sorbic Acid.Can add seasonings or tinting material like needs.
Suppository can comprise conventional suppository base, and this vehicle at room temperature is solid state, and fusing disengages medicine under body temperature, like theobroma oil, and other glyceryl ester or beeswax.
Stomach is offerd medicine outward, and liquid formulation is processed by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.According to the different of selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when processing injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be processed suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, can contain weight ratio 0.1% in the component, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 1-500 milligram activeconstituents.
It may be noted that in addition specific using dosage and method of use that The compounds of this invention is directed against different patients are decided by many factors, comprise patient's age; Body weight, sex, natural health situation; Nutritional status, the activity intensity of compound, Time of Administration; Metabolic rate, the severity of illness and diagnosis and treatment doctor's the person in charge judges.Here preferred using dosage is between the 0.01-100mg/Kg body weight/day.
Must recognize, the best dosage of compound of Formula I and be at interval by compound property with such as the decision of the external conditionss such as form, path and position of administration, and this best dosage can use conventional technology to confirm.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is confirmed.
The present invention further provides The compounds of this invention; Or its isomer, pharmacologically acceptable salt, hydrate or solvolyte treat and/or prevent the application that acute and Chronic HBV or HIV or HCV or HCMV infect the medicine of the disease that causes being used for preparing, and said medicine is used to the disease of treating and preventing virus to cause.Said disease is including, but not limited to diseases such as following disease: HBV, HCV, HIV and HCMV.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
The fusing point of compound is measured by RY-1 fusing point appearance, and TM is calibration not.Mass spectrum is measured by Micromass ZabSpec mass spectrograph.
1H-NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR appearance, operating frequency
1H-NMR 400MHz.
Embodiment 1 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
At N, in dinethylformamide (30ml) solution, add FTC (741.6mg, 3.0mmol), 4S-4-(3-chloro-phenyl-)-N; N-di-isopropyl-1,3, (1.45g is 4.5mmol) with 5-methylthio group tetrazole (527mg for 2-dioxa phospha cyclohexane-2-amine; 4.5mmol), be cooled to subzero 45 ℃, slowly drip tertbutanol peroxide, behind the reaction 1h; Be warming up to room temperature and react 24h again, remove solvent under reduced pressure, silica gel column chromatography is used methyl alcohol: methylene dichloride=1: 18 wash-out; Obtain 0.30g white powder solid, yield 21.0%, fusing point 98-100 ℃, R
f=0.38 (methyl alcohol: methylene dichloride=1: 9).
1HNMR(400MHz，DMSO)，δ(ppm)：1.98-2.45(m，2H)，2.91-3.22(m，1H)，3.20-3.47(m，1H)，4.19-4.62(m，4H)，5.21-5.60(m，2H)，6.16-6.32(m，1H)，7.20-7.51(m，4H)，8.22(S，1H)；ESI-MS：478.0(M+1)。
Embodiment 2 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
Adopt 1 identical method preparation, obtain 0.25g white powder solid, yield 17.5%, fusing point 92-94 ℃, R with embodiment
f=0.42 (methyl alcohol: methylene dichloride=1: 9).
1HNMR(400MHz，DMSO)，δ(ppm)：2.01-2.48(m，2H)，2.89-3.25(m，1H)，3.20-3.49(m，1H)，4.09-4.68(m，4H)，5.22-5.59(m，2H)，6.18-6.30(m，1H)，7.20-7.51(m，4H)，8.22(S，1H)；ESI-MS：478.0(M+1)。
Embodiment 3 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl } the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl] preparation of cytosine(Cyt)
Adopt with embodiment 1 similar method to prepare, with FTC (741.6mg, 3.0mmol), 4S-4-(4-pyridyl)-N; N-di-isopropyl-1,3,2-dioxa phospha cyclohexane-2-amine (1.27g; 4.5mmol) and 5-methylthio group tetrazole (527mg, 4.5mmol) reaction obtains 0.28g brown ceramic powder shape solid; Yield 21.0%, R
f=0.40 (methyl alcohol: methylene dichloride=1: 6).
1HNMR(400MHz，DMSO)，δ(ppm)：
1HNMR(400MHz，DMSO)，δ(ppm)：2.01-2.38(m，2H)，2.91-3.26(m，1H)，3.22-3.50(m，1H)，4.10-4.67(m，4H)，5.20-5.63(m，2H)，6.19-6.35(m，1H)，7.34(d，J＝9.6Hz，2H)，8.24(s，1H)，8.56(d，J＝9.6Hz，2H)；ESI-MS：445.1(M+1)。
Embodiment 4 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
Adopt 3 identical method preparations, obtain 0.23g brown ceramic powder shape solid, yield 17.2%, R with embodiment
f=0.45 (methyl alcohol: methylene dichloride=1: 6).
1HNMR(400MHz，DMSO)，δ(ppm)：1.95-2.30(m，2H)，2.90-3.27(m，1H)，3.25-3.56(m，1H)，4.08-4.69(m，4H)，5.17-5.63(m，2H)，6.22-6.34(m，1H)，7.34(d，J＝9.6Hz，2H)，8.24(s，1H)，8.56(d，J＝9.6Hz，2H)；ESI-MS：445.1(M+1)。
Embodiment 5 (2R)-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
With (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.87g, 10mmol), N, (1.01g 10mmol) joins in the 250ml dichloromethane solution N-DEF; Under the condition of anhydrous and oxygen-free, slowly drip oxalyl chloride (3.81g, 30mmol), reheat is to back flow reaction 3h; Then reaction solution is cooled to-78 ℃, add successively triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1; Ammediol (1.87g, 10mmol), reaction is reacted 1h after slowly being warming up to 0 ℃ behind the 1h again; Drip the 8.0g trifluoroacetic acid, stir 30min post-heating back flow reaction 2h, reaction finishes.Add the neutralization of yellow soda ash frozen water solution, the organic layer washing is to neutral, and anhydrous sodium sulfate drying filters; Remove solvent under reduced pressure, silica gel column chromatography, use methyl alcohol: methylene dichloride=1: 20 wash-out obtains 1.84g yellow powder shape solid; Yield 42.0%, fusing point 90-92 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1: 10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.16d，(d，3H)，1.75-2.04(m，2H)，3.45-3.96(m，3H)，4.05-4.26(m，1H)，4.26-4.55(m，3H)，5.57(m，1H)，7.19-7.43(m，4H)，8.07(s，1H)，8.12(s，1H)；ESI-MS：438.1(M+1)。
Embodiment 6 (2R)-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 5 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.87g, 10mmol), N, N-DEF (1.01g; 10mmol), oxalyl chloride (3.81g, 30mmol), triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1; (1.87g 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtains 1.34g yellow powder shape solid to ammediol; Yield 30.6%, fusing point 88-90 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1: 10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.18(d，3H)，1.75-2.04(m，2H)，3.40-3.96(m，3H)，4.05-4.25(m，1H)，4.26-4.58(m，3H)，5.57(m，1H)，7.19-7.47(m，4H)，8.07(s，1H)，8.10(s，1H)；ESI-MS：438.1(M+1)。
Embodiment 7 (2R)-9-{2-[4 '-(3-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
At 20ml N, in the dinethylformamide solution, add (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g; 2mmol), 3-(3-chloro-phenyl-)-1, ammediol (0.37g, 2mmol), 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol); Stirring at room 30min is warming up to about 100 ℃ and reacts 24h, and reaction finishes.Reaction solution is dissolved in ETHYLE ACETATE, uses 10% Hydrocerol A, 4% sodium hydrogen carbonate solution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, silica gel column chromatography obtains 0.40g yellow powder shape solid; Yield 45.6%, fusing point 87-89 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1: 10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.12-1.22(m，3H)，1.78-2.10(m，2H)，3.36-4.86(m，7H)，5.20-5.60(m，1H)，7.09-7.47(m，4H)，8.05-8.20(s，2H)；ESI-MS：438.1(M+1)。
Embodiment 8 (2R)-9-{2-[4 '-(phenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-phenyl-1; Ammediol (0.30g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.30g pulverulent solids, yield 37.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.21(m，3H)，1.78-2.20(m，2H)，3.36-4.90(m，7H)，5.22-5.60(m，1H)，7.09-7.40(m，5H)，8.05-8.25(s，2H)；ESI-MS：404.1(M+1)。
Embodiment 9 (2R)-9-{2-[4 '-(3 '-bromophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3-bromophenyl)-1; Ammediol (0.46g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.38g pulverulent solids, yield 36.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.13-1.25(m，3H)，1.75-2.20(m，2H)，3.36-4.95(m，7H)，5.22-5.50(m，1H)，7.04-7.60(m，4H)，8.05-8.20(s，2H)；ESI-MS：482.1(M+1)。
Embodiment 10 (2R)-9-{2-[4 '-(3 '-fluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3-fluorophenyl)-1; Ammediol (0.34g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.26g pulverulent solids, yield 30.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.25(m，3H)，1.65-2.23(m，2H)，3.32-4.96(m，7H)，5.16-5.40(m，1H)，7.00-7.48(m，4H)，8.02-8.19(s，2H)；ESI-MS：422.1(M+1)。
Embodiment 11 (2R)-9-{2-[4 '-(3 ', 5 '-difluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3; The 5-difluorophenyl)-1, and ammediol (0.38g, 2mmol), 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish; Obtain the 0.22g pulverulent solids, yield 25.0%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.28(m，3H)，1.60-2.24(m，2H)，3.36-4.98(m，7H)，5.06-5.49(m，1H)，6.74-7.20(m，3H)，7.80-8.40(s，2H)；ESI-MS：440.1(M+1)。
Embodiment 12 (2R)-9-{2-[4 '-(2 ', 3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(2; The 3-dichlorophenyl)-1, and ammediol (0.44g, 2mmol), 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish; Obtain the 0.31g pulverulent solids, yield 32.8%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.11-1.30(m，3H)，1.62-2.20(m，2H)，3.35-4.97(m，7H)，5.26-5.89(m，1H)，7.05-7.65(m，3H)，8.05-8.20(s，2H)；ESI-MS：472.1(M+1)。
Embodiment 13 (2R)-9-{2-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(4-pyridyl)-1; Ammediol (0.31g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.22g pulverulent solids, yield 27.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.08-1.28(m，3H)，1.65-2.24(m，2H)，3.38-5.04(m，7H)，5.20-5.62(m，1H)，7.08-7.38(m，2H)，8.04-8.60(s，4H)；ESI-MS：405.1(M+1)。
Embodiment 14 (2R)-9-{2-[4 '-(3 ', 5 '-xylyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3; The 5-xylyl)-1, and ammediol (0.36g, 2mmol), 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish; Obtain the 0.28g pulverulent solids, yield 32.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.08-1.28(m，3H)，1.65-2.34(m，8H)，3.46-4.95(m，7H)，5.05-5.45(m，1H)，6.75-7.30(m，3H)，8.00-8.20(s，2H)；ESI-MS：432.2(M+1)。
Embodiment 15 (2R)-9-{2-[4 '-(3 ', 5 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt with embodiment 7 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3; The 5-dichlorophenyl)-1, and ammediol (0.44g, 2mmol), 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish; Obtain the 0.38g pulverulent solids, yield 40.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.28(m，3H)，1.70-2.26(m，2H)，3.46-5.04(m，7H)，5.20-5.46(m，1H)，7.28-7.58(m，3H)，8.02-8.25(s，2H)；ESI-MS：472.1(M+1)。
Embodiment 16 2-amino-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 7 similar methods to prepare, with { 1-[(2-amino-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (0.60g, 2mmol), 3-(3-chloro-phenyl-)-1; Ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.48g pulverulent solids, yield 53.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.83-1.16(m，4H)，1.78-2.20(m，2H)，3.66-4.86(m，6H)，5.20-5.60(m，1H)，7.09-7.47(m，4H)，8.05(s，1H)，8.70(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 17 2-amino-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 5 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.99g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.04g yellow powder shape solid, yield 23.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.84-1.16(m，4H)，1.76-2.23(m，2H)，3.64-4.96(m，6H)，5.28-5.60(m，1H)，7.06-7.48(m，4H)，8.01(s，1H)，8.68(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 18 2-amino-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 5 similar methods to prepare, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.99g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.24g yellow powder shape solid, yield 27.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.90-1.12(m，4H)，1.78-2.22(m，2H)，3.66-4.88(m，6H)，5.30-5.63(m，1H)，7.08-7.50(m，4H)，8.02(s，1H)，8.70(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 19 2-amino-6-hydroxyl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 7 similar methods to prepare, with { 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (0.63g, 2mmol), 3-(3-chloro-phenyl-)-1; Ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.18g pulverulent solids, yield 19.3%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.82-1.18(m，4H)，1.76-2.25(m，2H)，3.68-4.88(m，6H)，5.20-5.61(m，1H)，7.06-7.50(m，4H)，8.05(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 20 2-amino-6-hydroxyl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 5 similar methods to prepare, with { 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (3.15g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.46g yellow powder shape solid, yield 9.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.80-1.12(m，4H)，1.77-2.23(m，2H)，3.62-4.98(m，6H)，5.23-5.65(m，1H)，7.09-7.51(m，4H)，8.04(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 21 2-amino-6-hydroxyl-9-{2-[(2S ', 4R ')-4 '-(3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt with embodiment 5 similar methods to prepare, with { 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-ring propoxy-} methane phosphonic acid (3.15g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.51g yellow powder shape solid, yield 10.1%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.87-1.20(m，4H)，1.74-2.21(m，2H)，3.65-4.96(m，6H)，5.26-5.67(m，1H)，7.06-7.49(m，4H)，8.04(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 22 2-amino-6-to anisole sulfydryl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl the preparation of purine
Adopt 7 similar methods preparations with embodiment, and general's { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid (0.82g, 2mmol), 3-(3-chloro-phenyl-)-1; Ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g; 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g; 2mmol) reaction finishes, and obtains the 0.38g pulverulent solids, yield 33.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.70-2.10(m，2H)，3.36-4.86(m，11H)，5.20-5.60(m，1H)，6.95-8.06(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 23 2-amino-6-to anisole sulfydryl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl the preparation of purine
Adopt 5 similar methods preparations with embodiment, and general's { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid (4.11g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.93g yellow powder shape solid, yield 16.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.73-2.16(m，2H)，3.38-4.80(m，11H)，5.20-5.62(m，1H)，6.90-8.08(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 24 2-amino-6-to anisole sulfydryl-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl the preparation of purine
Adopt 5 similar methods preparations with embodiment, and general's { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid (4.11g, 10mmol), N; The N-DEF (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol); Triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g; 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.03g yellow powder shape solid, yield 18.4%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.72-2.19(m，2H)，3.40-4.87(m，11H)，5.22-5.60(m，1H)，6.91-8.08(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 25 2-amino-1,9-dihydro-9-[(1S, 3R; 4S)-4-hydroxyl-3-(2 '; 4 '-cis-(4 ' S)-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl) oxygen methyl-2-methylene radical pentamethylene]-preparation of 6H-purine-6-one
Adopt with embodiment 1 similar method to prepare, with entecavir (1.664g, 6.0mmol), 4S-4-(4-pyridyl)-N; N-di-isopropyl-1,3,2-dioxa phospha cyclohexane-2-amine (2.54g; 9.0mmol) and 5-methylthio group tetrazole (1.054g; 9.0mmol) reaction, obtain the 0.13g pulverulent solids, yield 4.3%.
1HNMR(400MHz，DMSO)，δ(ppm)：1HNMR(400MHz，DMSO)，δ(ppm)：7.67(s，1H)，7.15-7.43(m，4H)，5.26-5.64(m，3H)，4.18-4.65(m，4H)，3.31-3.75(m，2H)，1.75-2.54(m，5H)；ESI-MS：508.1(M+1)。
The pharmacologically active evaluation of anti-DHB (DHBV) in experimental example 26 bodies
Animal model: 1 age in days duckling of the egg incubation that the Chongqing sheldrake of employing healthy adult produces, inoculation 0.1ml DHBV DNA positive-virus serum through the abdominal cavity.After inoculating for 1 week, respectively external jugular vein blood drawing detects to filter out through dot hybridization with the DHBV dna probe of digoxigenin labeled and infects positive duck, raise to 2 all ages as laboratory animal.
Measuring method: will infect 55 of positive ducks and be divided into 11 groups at random, and be divided into: 1. virus control group, use the starch capsule; 2. positive drug control group: use emtricitabine, dosage is 100mg/ (kg.d) and tynofovir ester, and dosage is 150mg/ (kg.d); 3. embodiment 1 and embodiment 3, dosage is 100mg/ (kg.d); 4. embodiment 5 and embodiment 6, dosage is 150mg/ (kg.d); 5. embodiment 17 and embodiment 20, dosage is 30mg/ (kg.d); 6. embodiment 23, and dosage is 5mg/ (kg.d); 7. embodiment 25, and dosage is 0.5mg/ (kg.d).The experiment administration time is 14 days, and drug withdrawal was observed 7 days.Observation index: serum DHBV DNA changes situation: before medication, medication 7 days, medication 14 days, drug withdrawal external jugular vein blood drawing respectively in 7 days, separation of serum is to be checked in-20 ℃ of preservations.Adopt spot hybridization, prepare with the digoxigenin labeled test kit of Roche Holding Ag that the DHBV dna probe is unified to be detected, carry out diaphragm with Vuego can (Brisa-620ST) scanner and scan; With the Discovery Series Quantity One software spot is carried out quantitative analysis, the spot value is volume (volume=intensity * mm
2).
Serum DHBV dna level comparison before and after table 1 treatment (x ± s)
Annotate:
aP＜0.05,
bP＜0.01
Interpretation of result: table 1 is classified mean number and the standard deviation of respectively organizing DNA spot volume value as, and statistics adopts before and after the treatment self paired t-test, is the comparison of dna level before medication group different time dna level and the medication on the same group.Wherein the activity of embodiment 3 anti-DHBV and positive control emtricitabine or tynofovir ester are suitable; The activity of the anti-DHBV of embodiment 1, embodiment 5, embodiment 17, embodiment 20, embodiment 23 and embodiment 25 obviously is superior to positive control emtricitabine or tynofovir ester.
Claims (9)
1. the compound or pharmaceutically acceptable salt thereof of following general formula I:
Wherein:
R
1Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyanic acid, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical or C
1-6Haloalkyl;
X is selected from the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
2. compound or pharmaceutically acceptable salt thereof according to claim 1 is characterized in that, R in the said general formula I
1With 4 aromatic group cis or trans each other in the SULPHOSUCCINIC ACID ESTER ring structure.
3. compound or pharmaceutically acceptable salt thereof according to claim 1 is characterized in that, in the said general formula I in the SULPHOSUCCINIC ACID ESTER ring structure 4 carbon atom have chirality, its configuration is S or R-configuration.
4. according to each described compound or pharmaceutically acceptable salt thereof of claim 1-3, it is characterized in that said compound is:
(1) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(2) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(3) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(4) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ' 2 '-dioxa phospha cyclohexane-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(16) 2-amino-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(17) 2-amino-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 ' dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(18) 2-amino-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(19) 2-amino-6-hydroxyl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(20) 2-amino-6-hydroxyl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(21) 2-amino-6-hydroxyl-9-{2-[(2S ', 4R ')-4 '-(3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(22) 2-amino-6-to anisole sulfydryl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(23) 2-amino-6-to anisole sulfydryl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(24) 2-amino-6-to anisole sulfydryl-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl] methoxy ethyl purine
(25) 2-amino-1,9-dihydro-9-[(1S, 3R; 4S)-4-hydroxyl-3-(2 '; 4 '-cis-(4 ' S)-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-dioxa phospha cyclohexane-2 '-yl) oxygen methyl-2-methylene radical pentamethylene]-the 6H-purine-6-one.
5. according to each described compound or pharmaceutically acceptable salt thereof of claim 1-3, it is characterized in that the salt of said compound is and mineral acid or the formed pharmacologically acceptable salt of organic acid.
6. according to each described compound or pharmaceutically acceptable salt thereof of claim 1-3, it is characterized in that the salt of said compound is and the formed pharmacologically acceptable salt of alkali reaction.
7. a medicinal compsns is characterized in that, comprises each described formula I compound or pharmaceutically acceptable salt thereof of claim 1-3, and pharmaceutically acceptable auxiliary.
8. medicinal compsns according to claim 7 is characterized in that, said pharmaceutically acceptable auxiliary comprises diluent or carrier.
9. each described compound or pharmaceutically acceptable salt thereof of claim 1-3 is in the application that is used for preparing the medicine that treats and/or prevents acute and the disease that chronic HBV infection causes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100774035A CN101475594B (en) | 2009-02-06 | 2009-02-06 | Liver targeted antivirus precursor medicament annular phosphoester and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100774035A CN101475594B (en) | 2009-02-06 | 2009-02-06 | Liver targeted antivirus precursor medicament annular phosphoester and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101475594A CN101475594A (en) | 2009-07-08 |
| CN101475594B true CN101475594B (en) | 2012-05-30 |
Family
ID=40836377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100774035A Expired - Fee Related CN101475594B (en) | 2009-02-06 | 2009-02-06 | Liver targeted antivirus precursor medicament annular phosphoester and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101475594B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312039B (en) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | A kind of preparation method of tenofovir prodrug |
| CN103333209B (en) * | 2013-07-05 | 2015-09-30 | 西安新通药物研究有限公司 | The new crystal of tynofovir prodrug (HTS) |
| CN104710477A (en) * | 2013-12-16 | 2015-06-17 | 安徽贝克联合制药有限公司 | Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof |
| CN107540710B (en) | 2016-06-24 | 2020-10-16 | 浙江柏拉阿图医药科技有限公司 | Liver delivery antiviral prodrug nucleoside cyclic phosphate ester compound and application thereof |
| WO2017220028A1 (en) * | 2016-06-24 | 2017-12-28 | 浙江柏拉阿图医药科技有限公司 | Liver delivery-based antiviral precursor drug nucleoside cyclophosphate compound and use thereof |
| CN108727450B (en) * | 2017-04-18 | 2024-02-20 | 浙江柏拉阿图医药科技有限公司 | Liver delivery anti-hepatitis C prodrug nucleoside cyclic phosphate compound and application thereof |
| CN109956986B (en) * | 2017-12-22 | 2021-04-27 | 浙江柏拉阿图医药科技有限公司 | Liver delivery gemcitabine prodrug nucleoside cyclic phosphate compound and application thereof |
| CN109956974A (en) * | 2017-12-22 | 2019-07-02 | 杭州国谋生物科技有限公司 | Liver delivers adefovir precursor medicament nucleosides cyclic phosphate compound and application |
| CN109956975B (en) * | 2017-12-22 | 2020-11-06 | 浙江柏拉阿图医药科技有限公司 | Liver delivery entecavir prodrug nucleoside cyclic phosphate ester compound and application thereof |
| CN114901657A (en) * | 2019-10-17 | 2022-08-12 | 人工智能生物制药公司 | Antiviral and liver-targeting drugs |
| WO2021223398A1 (en) * | 2020-05-07 | 2021-11-11 | 西安新通药物研究股份有限公司 | Crystal form for treating liver disease and use thereof |
| CN112028940B (en) * | 2020-05-07 | 2021-09-24 | 西安新通药物研究股份有限公司 | Tenofovir phosphate crystal form and preparation and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030225277A1 (en) * | 2002-05-13 | 2003-12-04 | Kopcho Joseph J. | Process for preparation of cyclic prodrugs of PMEA and PMPA |
| US20030229225A1 (en) * | 2002-05-13 | 2003-12-11 | Reddy K. Raja | Novel phosphonic acid based prodrugs of PMEA and its analogues |
| US20050282782A1 (en) * | 2004-06-08 | 2005-12-22 | Martin Kevin V | Lewis acid mediated synthesis of cyclic esters |
-
2009
- 2009-02-06 CN CN2009100774035A patent/CN101475594B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030225277A1 (en) * | 2002-05-13 | 2003-12-04 | Kopcho Joseph J. | Process for preparation of cyclic prodrugs of PMEA and PMPA |
| US20030229225A1 (en) * | 2002-05-13 | 2003-12-11 | Reddy K. Raja | Novel phosphonic acid based prodrugs of PMEA and its analogues |
| US7214668B2 (en) * | 2002-05-13 | 2007-05-08 | Metabasis Therapeutics, Inc. | Phosphonic acid based prodrugs of PMEA and its analogues |
| US20050282782A1 (en) * | 2004-06-08 | 2005-12-22 | Martin Kevin V | Lewis acid mediated synthesis of cyclic esters |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101475594A (en) | 2009-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101475594B (en) | Liver targeted antivirus precursor medicament annular phosphoester and use thereof | |
| CA2998189C (en) | Methods for treating arenaviridae and coronaviridae virus infections | |
| KR102057751B1 (en) | Tenofovir prodrug and pharmaceutical uses thereof | |
| US9216960B2 (en) | Spiro[2.4]heptanes for treatment of Flaviviridae infections | |
| JP6708329B2 (en) | Nucleotide analogues | |
| CN102939291B (en) | Phosphonate ester for the toxicity with reduction for the treatment of of viral infections | |
| EA026523B1 (en) | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment | |
| CN110156838A (en) | Phosphoric acid/phosphonate derivative and its medical usage | |
| TWI807399B (en) | Phospholipid compounds and uses thereof | |
| CN105669751A (en) | Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus | |
| JP5785939B2 (en) | Oxazolidinone-containing dimer compounds, compositions, and methods of making and using | |
| CN101787064B (en) | Cytarabine derivatives and purposes thereof in resisting cancers and tumors | |
| CN105348345A (en) | Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition | |
| CN104804042A (en) | Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof | |
| CN1906196A (en) | 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity | |
| EP1380303B1 (en) | Combination therapy to treat hepatitis B virus | |
| CN103421068A (en) | Heteroaryl phosphamide compounds with antiviral activity | |
| CN102617491A (en) | 3-oxo-3,4-dihydro-2-pyrazinecarboxamide derivative, medicinal composition thereof and preparation method and application of 3-oxo-3,4-dihydro-2-pyrazinecarboxamide derivative | |
| CN101787065B (en) | Cytarabine prodrug derivatives and purposes thereof in resisting cancers and tumors | |
| ES2962774T3 (en) | Inhibitors of human immunodeficiency virus replication | |
| KR20240052801A (en) | 2'-Chloro-2'-fluoro-N2-amino-N6-methylamino purine nucleotide for flavivirus treatment | |
| TW201625256A (en) | Administration of ubiquitin-activating enzyme inhibitor and chemotherapeutic agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120530 Termination date: 20130206 |